Accepted Manuscript

Vaginal Progesterone combined with Cervical Pessary A Chance for Pregnancies at

Risk for Preterm Birth?

Nathanael Stricker, Nina Timmesfeld, Ioannis Kyvernitakis, Janina Goerges, Birgit

Arabin

PII: S0002-9378(15)02488-6
DOI: 10.1016/j.ajog.2015.12.007
Reference: YMOB 10814

To appear in: American Journal of Obstetrics and Gynecology

Received Date: 19 August 2015

Revised Date: 13 November 2015
Accepted Date: 7 December 2015

Please cite this article as: Stricker N, Timmesfeld N, Kyvernitakis I, Goerges J, Arabin B, Vaginal
Progesterone combined with Cervical Pessary A Chance for Pregnancies at Risk for Preterm Birth?,
American Journal of Obstetrics and Gynecology (2016), doi: 10.1016/j.ajog.2015.12.007.

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Vaginal Progesterone combined with Cervical Pessary

A Chance for Pregnancies at Risk for Preterm Birth?

Nathanael STRICKER1, Nina TIMMESFELD2, Ioannis KYVERNITAKIS1,

Janina GOERGES1, Birgit ARABIN1, 3

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Department of Obstetrics and Gynecology, Philipps-University Marburg, Germany

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Department of Medical Biometry, Philipps-University Marburg, Germany

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In cooperation with the
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Clara-Angela Foundation, Witten and Berlin, Germany

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Correspondence to:
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Mr. Nathanael Stricker

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Neustadt 26 35037 Marburg/Germany

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Tel. +49 173 453 85 61 / Mail: stricker.nathanael@gmail.com

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Conflict of interest:

The senior author Prof. Birgit Arabin has a direct ownership interest in the company that
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manufactures pessaries including those used in the study. The company is privately held and
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the profit is used to support the Clara Angela Foundation for Research and Development. The

other authors have no conflict of interests.

Article type: Original article

Word count: Abstract: 442; Main text: 3502

Table 2 comprises the most valuable information and should stay in the printed version.
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Condensation

Women at risk for preterm birth treated with pessary plus vaginal progesterone had similar

outcomes to those treated with pessary alone, but their newborns had shorter stays in the

neonatal care unit.

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Abstract

BACKGROUND: Precocious cervical ripening as defined by cervical shortening on

transvaginal sonography has prompted a broad evaluation of secondary strategies to prevent

preterm delivery such as cerclage, vaginal progesterone or a cervical pessary. However, there

is a still a lack of direct comparisons between individual treatments or their combinations.

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OBJECTIVE: We sought to compare at risk patients and screening patients treated with

cervical pessary alone to patients treated with pessary plus vaginal progesterone.

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STUDY DESIGN: This is a pre- and post- intervention cohort study from a Preterm Labor

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Clinic where placement of a cervical pessary has been the standard treatment since 2008 for at

risk women defined by (1) a history of spontaneous preterm birth < 37 weeks, (2) conization,

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or (3) a cerclage due to a prior short cervical length < 3rd centile and additionally, with a
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cervical length < 10th centile in the ongoing pregnancy. Patients who did not meet criteria for

the "at risk" group, but who had a cervical length less than the 3rd percentile comprised the
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screening group. From July 2011 onward, vaginal progesterone (200 mg, suppositories) was
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prescribed in addition to the pessary. Both at risk patients (n=55) and screening patients
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(n=51) were treated at the time of diagnosis. The primary outcome was the rate of preterm

deliveries < 34 weeks. Secondary outcomes included deliveries < 28, < 32, and < 37 weeks,
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the days from start of therapy until delivery, a composite index of neonatal outcome and the

number of days in the neonatal intensive care unit. Primary and secondary outcomes were
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compared between groups using multivariable models to adjust for possible confounders.
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RESULTS: Delivery < 34 weeks occurred in 17/53 patients (32.1%) treated with pessary plus

progesterone compared to 13/53 patients (24.5%) with pessary alone (p= 0.57). Similarly,

there was no difference in the rate of preterm delivery < 28, < 32 or < 37 weeks. The

composite poor neonatal outcome was 15.1% in the pessary group versus 18.9% in the

combined group (p= 0.96). The mean duration of stay in the neonatal intensive care unit was

46.5 (9-130) days in the combined versus 52.0 (3-151) days in the pessary group (p<0.001).
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CONCLUSIONS: In this cohort study, treatment of precocious cervical ripening with

cervical pessary plus vaginal progesterone did not reduce the rates of preterm delivery before

28, 32, 34, or 37 weeks compared to pessary alone. The neonatal intensive care utilization was

shorter in patients who received additional vaginal progesterone although there was no

difference in composite poor neonatal outcome. These preliminary results may serve as a pilot

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for future trials and provide a basis for treatment until larger trials are completed.

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Alphabetic Keywords: Cerclage, Cervical Pessary, Precocious Cervical Ripening,

Prematurity, Preterm Delivery, Preterm Birth, Short Cervix, Transvaginal Sonography,

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Vaginal Progesterone
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Introduction
Preterm birth (PTB) is the major cause of perinatal morbidity and mortality in high

resourced countries with a prevalence of 5.3% (Latvia) up to 12 % (United States).1, 2 Primary

prevention has rarely been shown to be effective apart from a few studies that sought to

reduce either physical stress by public health interventions3 or smoking by smoke-free

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legislation.4 After the introduction of transvaginal sonography (TVS) as a tool to identify and

follow women at risk for PTB,5, 6 secondary preventive concepts such as progesterone7, or a

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cervical pessary8 were re-introduced as a treatment for women with precocious cervical

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ripening.9-12 In addition, the indication for a cerclage was re-evaluated on the basis of TVS-

results.13

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In our preterm labor clinic, we have placed cervical pessaries in singleton pregnancies
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with a short cervix since October 2008. Starting in July 2011, we added the administration of

vaginal progesterone based on the publication of Hassan et al10 hoping that the two
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approaches might provide complementary secondary preventive effects in high risk

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pregnancies and pregnancies that with screening had a short cervical length (CL). The aim of
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this study was 1) to develop intermediate information for patients, whose treatment cannot

await the results of large randomized controlled trials (RCTs) and 2) to serve as a pilot for
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planning future trials.14-17

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Materials and Methods

A pre- and post-intervention cohort study was conducted from October 2008 to

December 2014 in women with singleton pregnancies at increased risk for PTB by both

history and cervical shortening and a screening group without risks but found to have isolated

cervical shortening. Within this period, 13,179 examinations were performed in 4,393 patients

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who had been referred to our outpatient unit for various reasons including increased risk

factors for PTB. The risk group of this study population was characterized by a history of

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PTB <37 weeks (n=35), of whom 26/35 patients (74.3%) had a previous PTB < 32 weeks, a

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history of surgical conization (n=18), a cerclage due to a prior short CL< 3rd centile (n=11) or

a combination of cerclage and prior conization (n=2) (Table 1). In total, 6 patients in the

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pessary and 5 in the combined group had both a previous PTB and a conization or cerclage,
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they are considered for calculations in both categories. Patients who did not meet criteria for

the "at risk" group, but who had a CL less than the 3rd percentile comprised the screening
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group detected during the second trimester screening scan at our ultrasound unit. The
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gestational age of referral ranged between 12 and 27+1 in the risk group and 17+1 and 27+6
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gestational weeks in the screening group. A perforated Arabin Cerclage pessary was applied.

The sizes were chosen according to previously published recommendations related to height,
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upper and lower diameters.18 In our study population with only singleton pregnancies, the

height was always 21 mm and the upper diameter 32 mm except for patients with severe
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funneling where an upper diameter of 35 mm is recommended. Dependent on the obstetric

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history the lower diameter was 65 mm in women without and 70 mm in women with a

previous vaginal delivery. The device is CE approved for the prevention of preterm labor

(MEDCERT 0482, certificate 10610 GB 412, 150 324). The pessary was placed when the CL

was below the 10th centile19 (e.g. 34.9 mm, 29.2 mm and 25.2 mm at 16, 24 and 28 weeks of

gestation respectively) in the risk group and when the CL was below the 3rd centile19 (e.g.

30.5 mm, 23.4 mm and 18.7 mm at 16, 24 and 28 weeks respectively) in screening patients
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(Table 1). Only patients with a start of treatment > 12 and < 28 weeks of gestation were

included for further analysis. For the interval of 12-16 weeks we extrapolated the Salomon

centiles by using the centiles of Gramellini et al. (32.8 mm for the 3rd centile and 37.5 mm for

the 10th centile at 12th weeks of gestation).20 The success of pessary treatment depends on

both standardized cervical sonography as well as the skills of the obstetrician in charge as

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there is a well defined learning curve.21 Therefore patients were only included if diagnosed

and treated by one experienced specialist who also followed all high risk referrals of this

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study. All patients had been examined by TVS according to the Fetal Medicine Foundation in

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the first trimester22 and the method described by Iams et al from 16 weeks onwards6 re-

defined by To et al.23 Funneling was classified as a V-, Y- or U-shaped dilatation of the

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internal os with at least a width of 5 mm.24
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Patients and involved specialists were informed about pessary insertion and possible

side effects such as vaginal discharge and treatment followed a prescribed protocol.24 During
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the insertion, the pessary was squeezed, introduced longitudinally and only unfolded in the
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upper fornix whereby the smaller inner ring was directed towards the cervix. The proximal
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part of the pessarys dome was carefully pushed until the cervix was surrounded, and the

anterior part of the pessary was then pressed slightly towards the sacrum.18 The pessary
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remained until either 37 weeks, premature preterm rupture of membranes (PPROM) or regular

contractions suggesting active labor. In one patient, the pessary was removed due to
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mechanical irritation and a smaller version was inserted. Patients who complained about
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discharge were re-assured that this should not be confused with infection or PPROM. Patients

were seen one week after pessary insertion whereby a TVS was performed placing the

transducer on top of the anterior cervix thus avoiding shadowing by the pessary and cervical

manipulation. Thereafter, screening patients were followed by their own gynecologist if there

were no further problems. High risk pregnancies with previous PTB, perinatal losses or

radical conization were followed within our outpatient unit until at least 32 weeks.
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From July 2011 onward, informed consent included information on recent studies of

vaginal progesterone administered as 200 mg vaginal suppositories in the evening and

thereafter patients received combined therapy. In total, 53 patients received a pessary only

and 53 patients received both, pessary and vaginal progesterone (Table 1). For the whole

study we calculated a comparability score25 of 11/12 points, 1 point for midyear interval, e.g.

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the time interval between different policies, and 2 points for each other variable (geographic

setting, health care setting, health care providers, confounding interventions impact,

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consensus statements impact).

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Exclusion criteria were major fetal abnormalities, PPROM before the start of therapy,

ballooning membranes (beyond the external os), vaginal bleeding and painful or regular

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contractions before the start of therapy.
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Primary outcome was the rate of PTB before 34 weeks. Preterm Cesarean delivery <37 weeks

was indicated due to severe preeclampsia (n=1), suspected chorioangioma (n=1), placenta
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praevia (n=1), suspicious fetal heart rate monitoring without regular contractions (n=1),
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PPROM (n=12), chorioamnionitis (n=3), regular contractions with >5 cm dilatation combined
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with abnormal presentation (n=3), pathological fetal heart rate pattern (n=6) or prolonged

labor (n=1). Secondary outcomes included rates of PTB < 28, < 32, and < 37 completed
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weeks, birth weight, admission to the neonatal intensive care unit (NICU), the number of days

in the NICU and the composite poor neonatal outcome defined by perinatal or neonatal death,
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respiratory distress syndrome > grade II, bronchopulmonary dysplasia, intraventricular

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hemorrhage grade III or IV, and necrotizing enterocolitis. Days of neonatal hospitalization

were analyzed separately. All data were retrieved from our hospital data system and double

checked with paper charts. Statistical analyses were performed with R Version 3.1.1 using the

packages survival and pscl and Microsoft Office Excel 2007.

Baseline characteristics were analyzed using t-tests and -tests. Logistic regression

was used to compare the primary and secondary outcomes between the pessary group (P) and
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the group with pessary and additional vaginal progesterone (PP). For birth weight and

prolongation of pregnancy, a linear model and for the comparison of the number of days in

the NICU, a zero-inflated Poisson regression model was used assuming that the treatment had

an effect on the number of NICU days (Poisson part of the model) but not on the rate of NICU

admission per se (n=30). For all models, confounders such as the Z-score of CL at the time of

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treatment initiation, nulliparity, and the history of PTB, were included as covariates. In

contrast to absolute values, Z-scores of CL consider the normal range of values for each

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gestational week. The Z-scores were calculated based on the formula by Salomon et al.19 For

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the zero-inflated Poisson regression the use of corticosteroids was included as an additional

covariate in the Poisson parts of the models. In a separate analysis for the comparison of the

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number of days in the NICU (zero-inflated Poisson model), gestational age or birth weight
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were also included as additional covariates. A variable indicating the population group (risk

versus screening) was included in all models for the total population. P-values < 0.05 were
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considered to indicate statistically significant differences between the two groups.

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Results

The profile of the 106 patients is shown in Table 1: 53 women received a pessary and

53 received a pessary plus vaginal progesterone. Primigravid women were more common in

the screening than the risk group (62.7% versus 14.5%). All 29 patients in both treatment

arms who delivered between 24 and 33+6 weeks received corticosteroids which were only

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administered when the CL was < 15 mm or a delivery < 34 weeks was indicated. Patients

delivering > 34 weeks received corticosteroids in 21/76 cases (27.6%), 11/40 patients (27.5%)

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in the pessary group and 10/36 (27.8%) in the pessary plus progesterone group. There were no

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significant differences with respect to baseline characteristics (Table 1). Figure 1 shows the

CL at start of therapy separately for screening and risk populations and both treatment groups

within the centiles used for indication.

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The rate of delivery < 34 weeks (primary outcome) was not significantly different:

13/53 patients (24.5%) treated with pessary only and 17/53 patients (32.1%) treated with
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pessary and vaginal progesterone (OR: 1.29, 95% CI: 0.53-3.15; p=0.57) (Table 2).
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There were also no significant differences in the rates of PTB before 28, 32 or 37
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weeks (Table 2). This is reflected in the Kaplan Meier curves showing a trend of a longer

prolongation in risk pregnancies treated with pessary only and in screening patients treated
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with pessary plus vaginal progesterone (Figure 2). Neither birth weight nor the duration of

pregnancy prolongation differed significantly (Table 2). Composite poor neonatal outcome
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occurred in 8/53 neonates (15.1%) treated with pessary only and 10/53 neonates (18.9%)
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treated with pessary and vaginal progesterone (OR: 1.03, 95% CI: 0.34-3.09; p=0.96) (Table

2). One perinatal death occurred at 22+2 weeks in a patient with pessary and progesterone.

A low CL Z-score at the start of therapy showed a trend to correlate with PTB < 34

weeks (OR: 0.543, p=0.091) for all pregnancies.

In total, 15/53 (28.3%) newborns in each group were admitted to the NICU (OR: 0.94,

95% CI: 0.39-2.25; p=0.89). The average days of neonatal admission were 52.0 (3-151) days
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in the pessary group compared to 46.5 (9-130) days in the combined group (E: 0.57, 95% CI:

0.50-0.65; p<0.0001). Although the absolute numbers were small, the statistical difference

remained in the subgroups of risk or screening patients (Table 2). Even when we controlled

for gestational age or birth weight in the regression model the results did not change.

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Discussion

Principal findings

Findings of this study suggest preliminary justification for the benefit of combined use of a

cervical pessary and vaginal progesterone although it did not reduce the rate of PTB

compared to singular therapy with cervical pessary alone. However, neonates whose mothers

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were treated with additional vaginal progesterone had a shorter NICU stay. Large studies are

expected to be finalized comparing the effect of both singular strategies14, 16, 17 or in progress

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comparing basic vaginal progesterone versus progesterone plus a cervical pessary (Hoffman

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et al, personal communication). Normally, multicenter studies take years to complete and

even longer for results to be disseminated; in the meantime, patients should be informed and

treated based on preliminary knowledge.

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Meaning of the findings

The evidence that progesterone reduces the rate of PTB was first suggested by Papiernik in
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19707 and by Keirse in 1990.26 The synthetic 17--hydroxyprogesterone caproate (17-OHPC)

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has a long half-life and is administered intra-muscularly on a weekly basis. Natural

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progesterone has a short half-life, is rapidly absorbed across the vaginal mucosa and

administered daily.27 The benefit of 17-OHPC as a preventive therapy in patients with a

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history of PTB remains controversial since the RCT of Meis et al28 was questioned by the

Food and Drug Administration (FDA) for its high baseline PTB rate in the placebo group
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(54.9%) and over safety issues.27 Currently, another large multicenter RCT is in progress
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enrolling women with a history of PTB.29 The use of natural progesterone to prevent PTB

experienced a revival after the first RCT was published in 2003 by DaFonseca et al.30

However, their selection of patients was not based on TVS. In another study, patients with a

short CL were even excluded.31 It was only when DaFonseca et al investigated the effect of

vaginal progesterone in combination with TVS that the investigators were able to determine

that PTB < 34 weeks could be reduced in patients with a short CL< 15 mm. Unfortunately,
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the study was not powered to detect a reduction in neonatal morbidity.9 This further step was

taken in the study by Hassan et al.10

A ring pessary was first suggested by Cross in 1959 to prevent PTB.8 The availability

of TVS5 and the knowledge of a specific cervical pessary that enclosed the inner os32 by a

convex shape changing the angle between cervix and lower uterine segment, as demonstrated

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on MRI,33 revived interest in its use for patients with a short CL.11 A RCT in singleton

pregnancies with a short CL revealed a reduction in PTB < 34 weeks and improvements in

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neonatal outcome.12 Alfirevic et al retrospectively compared patients at risk for PTB with a

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short CL who had either received a cerclage, vaginal progesterone or a pessary but due to the

design, these results should be interpreted with caution.34 Conflicting results were reported

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from a group in Hong Kong who found benefit in patients with high risk, but not in a still
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underpowered study with low risk patients.35, 36

Berghella et al demonstrated a decrease of PTB rate < 35 weeks in singleton

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pregnancies with a CL < 25 mm treated by cervical cerclage. In this paper, the reduction did
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not reach significance in patients with funneling or with a CL < 15 mm.37 After inclusion of
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data by Owen et al38 another meta-analysis by Berghella et al39 showed a significant reduction

in PTB of cerclage in singleton pregnancies having both a previous PTB and a CL < 25 mm
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even in the subgroup with a CL < 15 mm. Evidence that a cerclage is beneficial in patients

without a previous PTB is still missing.40

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Within our preselected risk group, 19 patients had a prior conization and all had a
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short CL, although this has been observed differently.41 The invasiveness of the conization

might vary dependent on operative skills and the severity of disease. In addition, indications

for referral may vary. In any case, in women with a history of conization the CL detected by

TVS is the most significant risk factor.42 Due to local policy, some colleagues referred

patients in the first trimester particularly if they had a history of perinatal losses or early PTB.

Since prophylactic cerclage could not prevent PTB in patients with a conization and a short
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CL,42, 43
we proposed treatment by a pessary and after 2011 pessary plus progesterone

although RCTs are lacking.44

All women in our at risk group were already afraid of the consequences of an early

PTB. They were informed about treatment options such as cerclage,37-40 pessary34, 44 and from

2011 onward, vaginal progesterone.10 After the informed consent process, our patients

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preferred a pessary to a cerclage likely due to the non-invasive nature of the pessary and the

fact that it could be easily applied directly after TVS.

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Clinical implications

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A successful prevention of PTB should reduce both prematurity and neonatal morbidity.45

Although our numbers are too small to reach significance for composite neonatal outcome,

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the shorter NICU stay of the neonates whose mothers were treated with a combined therapy
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suggests these children experienced less severe morbidity. This interpretation is limited by a

historic model although the general policy and staff had not been changed during the
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observation period. DeFranco et al46 found similar results: Neonates whose mothers had
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received vaginal progesterone spent on average only 1.1 day on the NICU, neonates from
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mothers with expectant management 16.5 days.

Research implications
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We had hoped that the combination of cervical pessary and vaginal progesterone might have a

complementary and more obvious additive benefit. This was not the case, but it is likely that
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if a therapy is already effective in preventing PTB, any additional or marginal benefit of other
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interventions would be difficult to discern. This might be the same if a study starts with

vaginal progesterone in all patients and then randomly adds a pessary. Our findings imply that

a large number of patients will be required to show an improvement in neonatal outcome of a

combined therapy, which makes it improbable, that such trials will be completed soon.

To explain why neonates in both subgroups had shorter NICU stays when vaginal

progesterone was added deserves pathophysiologic considerations which can be found

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elsewhere.47-54 There appear to be no long term outcome data for vaginal progesterone.

However, when progestogens were used in women with infertility, there was an increased rate

of acute lymphoblastic leukemia and sympathetic nervous system tumors consistent with the

fact that as an accelerator of cell division, progestogens could increase the mutation rate

through epigenetic changes.55

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Strengths and weaknesses

In contrast to pharmacological trials, pessary treatment cannot be blinded, but analysis was

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blinded in our study from the clinician who was responsible for treatment and follow-up

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including critical decisions regarding continuation or cessation of treatment.

It is disappointing that gynecologists, either in trials or in clinical practice, do rarely

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take part in team training or sometimes not even follow protocols. A lack of quality control
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may explain why trials in different settings may fail. Already introduced audit procedures56

should not be limited to diagnostic tools57 but also be implied for interventions and patient
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follow-ups mainly when procedures are still novel. Compliance is a crucial issue. It had been
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shown even in a national study that clinicians due to disbelief either removed a pessary too
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early or inappropriately applied a cerclage instead of following the pessary arm of the study.58

Although our study was small, the strength is that we avoided these limitations.
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Unlike most studies, we did not use cut-offs for CL but centiles19 as a criterion for

therapy. As already suggested, reference ranges are more useful than single cut-off values for
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efficient prevention and management of PTB.59 Numeric cut-offs are pragmatic for RCTs
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when patients are included at a certain gestational age, but the cervix does not change in steps

but continuously. In addition, in private health care systems, patients are referred at varying

gestational ages. Different centile cut-offs could be chosen for interventions in screening and

at risk groups since cervical shortening progresses faster in at risk groups.60 Altogether, we

regard the use of centiles as a strength.

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Our study has design limitations. The data were collected from patients referred by

local gynecologists resulting in different gestational ages at treatment initiation or even a

selection bias. There was no control group without intervention because these women require

care based on the best information available, albeit imperfect. Last not least, due to the small

number of patients controlled by one specialist, our study can only be regarded as a pilot.

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Next step in research

The Go-Net initiative was founded to standardize core outcomes for PTB among

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researchers, midwifes and patients for later prospective meta-analyses. Similarly to the

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criteria for primary prevention of PTB,61 thirteen consensus outcomes were agreed to and

have been incorporated into many trials in different countries. The full results have been

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submitted as Core Outcomes in Womens Health (CROWN). Nevertheless, it will take years
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until studies using these outcomes will be available for meta- or subgroup analyses.

In summary, any power analysis for future trials should consider the large number of
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patients necessary to confirm an additional benefit of a combined therapy not to forget the
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importance of teaching and audit procedures. In the meantime, it seems reasonable to indicate
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both treatment strategies in patients at high risk of perinatal loss or early PTB. Health care

providers and policy makers should realize that the clinical risks and costs of TVS, even in
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patients without previous PTB,62 and of both preventive strategies are relatively low63, 64, 65

compared to tertiary procedures which are frequently initiated too late. Even more important
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than cost reduction is the need to prevent the suffering of parents and children as a
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consequence of prematurity.
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Disclosure of interests

Conflict of interest: The senior author Prof. Birgit Arabin has an ownership interest in the

company that manufactures pessaries including those used in the study. The company is

privately held and the profit is used to support the Clara Angela Foundation for Research and

Development. The other authors have no conflict of interests.

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Dr. Arabin was only involved in patient care and helping to write but not in data analysis.

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Contribution to authorship

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N.S. and B.A. designed the study and drafted the manuscript. B.A. did the clinical work

including TVS, instruction of patients, pessary application and surveillance. N.S., J.G. and

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I.K. contributed to the acquisition of data. N.T. made substantial contributions in data analysis
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and interpretation. All authors read and approved the final manuscript.
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Details of ethics approval

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The ethics committee of the University Hospital of Marburg gave permission to perform the
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study as part of a clinical approach, which had already been accepted as a clinical

management in patients at risk for preterm delivery.

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Funding
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None
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2. GOLDENBERG RL, CULHANE JF, IAMS JD, ROMERO R. Epidemiology and causes of preterm birth.
Lancet 2008;371:75-84.
3. PAPIERNIK E, BOUYER J, DREYFUS J, et al. Prevention of preterm births: a perinatal study in
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4. BEEN JV, NURMATOV UB, COX B, NAWROT TS, VAN SCHAYCK CP, SHEIKH A. Effect of smoke-free

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legislation on perinatal and child health: a systematic review and meta-analysis. Lancet
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premature delivery. National Institute of Child Health and Human Development Maternal

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Fetal Medicine Unit Network. N Engl J Med 1996;334:567-72.
7. PAPIERNIK-BERKHAUER E. Etude en double aveugle d'un medicament prevenant la survenue
premature de l'accouchement chez des femmes a risque eleve d'accouchement
premature. Edition Schering, Serie IV, fiche 3, 1970.

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8. CROSS R. Treatment of habitual abortion due to cervical incompetence.: Lancet, 1959;2:127.
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Risk population Screening population Total population

Pessary and Pessary and Pessary and
Pessary Pessary p- Pessary p-
Progesterone p-value Progesterone Progesterone
N=27 N=28 N=26 N=25
value N=53 N=53
value

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Age (years) 31.4 6.13 32.7 3.68 0.347 30.3 6.74 31.7 5.14 0.408 30.9 6.40 32.2 4.41 0.203
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Body mass index (kg/m ) 23.33.67 22.8 4.76 0.657 24.0 3.77 23.6 3.29 0.634 23.7 3.70 23.2 4.11 0.506
Smokers (n (%)) 3 (11.1%) 2 (7.1%) 0.669 2 (7.7%) 2 (8.0%) 1 5 (9.4%) 4 (7.5%) 1

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Obstetric history*
Nulliparous 4 (14.8%) 4 (14.3%) 1 14 (53.8%) 18 (72.0%) 0.293 18 (34.0%) 22 (41.5%) 0.548
Obstetric history of preterm birth

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32 weeks 14 (51.9%) 12 (42.9%) - - 14 (26.4%) 12 (22.6%)
0.671 - 0.822
Between 32 and 37 weeks 5 (18.5%) 4 (14.3%) - - 5 (9.4%) 4 (7.6%)
History of surgical conization or treatment for threatening

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preterm birth with a CL <3 centile by a cerclage (n, %)
Cervical Cerclage 5 (18.5%) 6 (21.4%) - - 5 (9.4%) 6 (11.3%)

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Surgical conization 9 (33.3%) 9 (32.1%) 0.665 - - - 9 (17.0%) 9 (17%) 0.689
Both, conization and cerclage 0 2 (7.14%) - - 0 2 (3.8%)
Course of pregnancy

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Gestational age at start of therapy (weeks + days, 19+3 19+0 24+0 23+6 21+5 22+2
0.707 0.614 0.948
median[range]) [12+0; 27+1] [12+0; 26+4] [17+1; 27+6] 17+1; 27+6] [12+0; 27+6] [12+0; 27+6]
Cervical length at start of therapy 21.3 6.40 17.1 12.0 0.113 15.3 7.42 13.4 6.45 0.312 18.4 7.49 15.4 9.91 0.078

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Cervical length Z-score at start of therapy -2.49 0.55 -2.72 0.96 0.283 -2.55 0.57 -2.78 0.55 0.148 -2.52 0.55 -2.75 0.79 0.088

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Funneling at start of therapy 11 (40.7%) 11 (39.3%) 1 15 (57.7%) 17 (68.0%) 0.637 26 (49.1%) 28 (52.8%) 0.846
Tocolytics during course of pregnancy 4 (14.8%) 3 (10.7%) 0.705 7 (26.9%) 4 (16.0%) 0.543 11 (20.8%) 7 (13.2%) 0.438
Antenatal corticosteroids 11 (40.7%) 14 (50.0%) 0.676 13 (50.0%) 12 (48.0%) 1 24 (45.3%) 26 (49.1%) 0.846
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PPROM** <37 weeks 5 (18.5%) 7 (25.0%) 0.798 7 (26.9%) 4 (16.0%) 0.543 12 (22.6%) 11 (20.8%) 1
Gestational age at PPROM* (weeks + days) 29+6 6.0 29+5 6+0 0.965 31+5 3+0 34+0 2+6 0.251 31+0 4+2 31+2 5+2 0.867
Mode of delivery
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Spontaneous 15 (55.6%) 15 (53.6%) 12 (46.2%) 11 (44.0%) 27 (50.9%) 26 (49.1%)

Vaginal operative 1 (3.7%) 0 0.787 1 (3.85%) 1 (4%) 1 2 (3.77%) 1 (1.89%) 0.882
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Cesarean 11 (40.7%) 13 (46.4%) 13 (50.0%) 13 (52.0%) 24 (45.3%) 26 (49.1%)

Table 1) Baseline characteristics of the study population: Left: risk group defined by previous preterm birth > 16 , < 37 gestational weeks, a history of surgical conization or a previous cerclage
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due to a short cervix, all characterized by a short cervical length (CL) < the 10th centile detected by transvaginal sonography (TVS); Center: screening group defined by a CL < the 3rd centile
Right: total population, separate for the treatment with either pessary alone or pessary combined with vaginal progesterone. Baseline characteristics were analyzed using t-tests and -tests.
* 6 patients in the pessary and 5 in the combined group had a previous preterm birth and a conization or cerclage, they are here considered in both categories
**PPROM: premature preterm rupture of membranes
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Screening
Risk population Total population
population
Pessary and Pessary and Pessary and
Pessary Pessary Pessary
Progesterone Progesterone Progesterone
Odds p- Odds p- Odds p-

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N=27 N=28 95% CI N=26 N=25 95% CI N=53 N=53 95% CI
Ratio value Ratio value Ratio value
Primary
outcome

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Delivery <34
6 7 0.23- 13 0.53-
weeks 10 (35.7%) 1.63 0.44-6.2 0.46 7 (28%) 0.88 0.84 17 (32.1%) 1.29 0.57
(22.2%) (26.9%) 3.23 (24.5%) 3.15

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Secondary
outcomes

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Delivery <28 1 0.21- 0.01- 0.18-
4 (14.3%) 2.33 0.51 2 (7.7%) 1 (4.0%) 0.36 0.44 3 (5.7%) 5 (9.4%) 0.98 0.98
weeks (3.7%) 53.76 4.43 5.61

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Delivery <32 3 0.18- 5 0.20- 8 0.37-
6 (21.4%) 1.11 0.9 5 (20%) 0.89 0.88 11 (20.8%) 1.1 0.86
weeks (11.1%) 6.91 (19.2%) 3.85 (15.1%) 3.30
Delivery <37 10 0.36- 13 0.16- 23 0.40-
14 (50%) 1.25 0.72 10 (40%) 0.56 0.33 24 (45.3%) 0.91 0.83
weeks (37.0%) 4.26 (50%) 1.80 (43.4%) 2.05

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Composite poor 3 0.20- 5 0.16- 8 0.34-
6 (21.4%) 1.18 0.85 4 (16.0%) 0.76 0.71 10 (18.9%) 1.03 0.96
outcome (11.1%) 7.18 (19.2%) 3.41 (15.1%) 3.09
6 0.41- 9 0.14- 15 0.39-

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Admission to NICU 9 (32.1%) 1.51 0.53 6 (24.0%) 0.54 0.33 15 (28.3%) 0.94 0.89
(22.2%) 5.66 (34.6%) 1.89 (28.3%) 2.25
Neonatal

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51.8 47.6 E 0.31- 52.1 45.0 E 0.51- 52.0 46.5 E 0.50-
admission time 0.39 <0.01 0.61 <0.01 0.57 <0.01
37.7 43.1 0.50 39.1 54.5 0.73 37.1 46.1 0.65
(days)
Birth weight 2919 2668 - -695.7- 2602 2805 -267.3- 2763 2734 -355.9-
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0.54 277.2 0.31 21.5 0.91
(gram) 953 1010 162.9 369.8 907 966 821.65 935 982 398.9
Prolongation* 128 113 -35.74- 83.1 93.7 -18.4- 106 104 -20.71-
-9.41 0.48 7.69 0.56 -1.77 0.85
(days) 46.8 52.6 16.91 45.3 45.1 33-78 50.9 49.7 17.05
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Table 2) Outcome of the study population treated with cervical pessary or pessary combined with vaginal progesterone.
* Prolongation: Interval between start of therapy and delivery
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E Regression coefficient (zero-inflated Poisson regression model)

Regression coefficient (linear regression model)
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Figure Legend:

Figure 1) Cervical length at start of therapy within centiles according to Salomon et al19 in

singleton pregnancies with a short cervical length < the 3rd centile detected by transvaginal

sonography (Screening) or singleton pregnancies with a short cervical length < the 10th

centile and a history of preterm birth, surgical conization or a previous cerclage due to a short

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cervix (Risk) both treated with either pessary alone (P) or pessary combined with vaginal

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progesterone (PP).

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Figure 2) Kaplan-Meier curves demonstrating the prolongation of pregnancy of the risk

population treated with either pessary (P) or pessary plus vaginal progesterone (PP) and the

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screening population treated with either pessary (P) or the combination of pessary and vaginal
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progesterone (PP).
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